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Oral presentation

Xenotropic murine leukemia virus-related virus (XMRV) has been found in a high percentage
of humans with chronic fatigue syndrome (CFS). However, more recent studies have failed
to confirm these results, and it now appears likely that the original findings were
due to patient sample contamination. Because it initially appeared that XMRV was involved
in CFS, we explored potential mechanisms of XMRV neurotoxicity that might underliethe
neuromuscular pathology seen in CFS. Indeed, we found that XMRV infection induced
apoptosis in SY5Y human neuroblastoma cells. We hypothesized that signaling through
the cell-entry receptor for XMRV, the xenotropic and polytropic retrovirus receptor
(Xpr1), mediated this toxicity. In support of this hypothesis, SY5Y cells expressing
mouse Xpr1, which unlike human Xpr1 does not bind or promote entry of xenotropic retroviruses,
were resistant to XMRV toxicity, even though XMRV could still infect these cells.
Similarly, SY5Y cells expressing several XMRV binding-defective deletion mutants of
human Xpr1 were resistant to XMRV toxicity. These results indicate that Xpr1 mediates
the toxicity of XMRV.

Xpr1 is related the yeast Syg1 protein, which associates with the β subunit of the
yeast G-protein. We found that human Xpr1 is also associated with the human Gβ subunit,
and that over expression of mouse or human Xpr1 increased intracellular cAMP, a typical
output of stimulatory G-protein signaling. Moreover, increasing the cAMP level in
SY5Y cells by direct activation of adenylate cyclase protected the SY5Y cells from
the toxic effects of XMRV and polytropic retrovirus infection. These results indicate
that Xpr1 is a G-protein-coupled receptor (GPCR), and that xenotropic or polytropic
retrovirus binding can disrupt the cAMP-mediated signaling function of Xpr1 leading
to apoptosis of infected cells. In addition, we found that this pathway is responsible
for the toxicity of the polytropic mink cell focus-forming (MCF) retrovirus in mink
cells, the basis for the classic MCF focus assay.Xpr1 orthologs are widely distributed
in animals, plants and unicellular organisms, but these proteins show no sequence
similarity to known GPCRs. Some proteins with similarity to Xpr1 are involved in phosphate
uptake into cells, but we found no role of Xpr1 in phosphate uptake or its regulation.
Lastly, some polytropic retroviruses induce neurologic disease in mice, and we propose
that alterations of Xpr1-mediated G-protein signalinglikely are responsible. However,
because of recent results indicting that XMRV is not a human retrovirus, a role for
XMRV in human disease is unlikely.